Efficacy and Safety of DaxibotulinumtoxinA for Injection in Cervical Dystonia: ASPEN-1 Phase 3 Randomized Controlled Trial

Abstract

Background and objectives: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD).

Methods: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses.

Results: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%).

Discussion: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD.

Trial registration information: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24).

Classification of evidence: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

Figure 1. Participant Disposition

DAXI = DaxibotulinumtoxinA for Injection; TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale. ^aFour participants randomized to DAXI 125U received DAXI 250U. ^bFour participants randomized to DAXI 250U received DAXI 125U. ^cParticipant needed nonstudy botulinum toxin or oral dystonia medication. ^dParticipant received prohibited medication (a Botox preparation).

Figure 2. Change From Baseline in TWSTRS Total Score Averaged Across Weeks 4 and 6

p Values based on an ANCOVA model with terms for treatment, pooled study center (region), prior botulinum toxin treatment experience, and baseline TWSTRS total score as a covariate. Multiple imputation was used for participants missing week 4 and week 6 TWSTRS total score data. DAXI = DaxibotulinumtoxinA for Injection; LS = least squares; SE = standard error; TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale. ∆ represents % change from baseline.

Figure 3. Time to Loss of ≥80% of Peak Treatment Effect (Defined as TWSTRS Total Score Averaged Across Weeks 4 and 6) for (A) DAXI 125U and (B) DAXI 250U

DAXI = DaxibotulinumtoxinA for Injection; TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale.

Figure 4. Responders Achieving ≥2-Point Improvement at Weeks 4 or 6 for (A) Clinical Global Impression of Change (CGIC) and (b) Patient Global Impression of Change (PGIC)

CI = confidence interval; DAXI = DaxibotulinumtoxinA for Injection.

Figure 5. Change From Baseline in TWSTRS Subscale Scores Averaged Across Weeks 4 and 6

p Values based on a mixed model repeated measures analysis with fixed effect terms for treatment, prior botulinum neurotoxin treatment experience, pooled study center (region), visit, and treatment-by-visit interaction, and baseline TWSTRS subscale score as a covariate with an unstructured covariance. ∆ represents % change from baseline. DAXI = DaxibotulinumtoxinA for Injection; LS = least squares; SE = standard error; TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale.